Download Challenges and Opportunities in Radiation-induced

THERAPEUTIC STRATEGY UPDATE
Challenges and Opportunities in
Radiation-induced Hemorrhagic Cystitis
Bernadette M.M. Zwaans, MD,1 Heinz G. Nicolai, MD,2,3 Michael B. Chancellor, MD,1,4 Laura E. Lamb, MD1,2
1Department of Urology, William Beaumont Hospital, Royal Oak, MI; 2Departamento de Urología, Universidad
de Chile, Santiago, Chile; 3Hospital Clínico San Borja Arriarán, Santiago, Chile; 4Oakland University William
Beaumont School of Medicine, Royal Oak, MI
As diagnosis and treatment of cancer is improving, medical and social issues related to
cancer survivorship are becoming more prevalent. Hemorrhagic cystitis (HC), a rare but
serious disease that may affect patients after pelvic radiation or systemic chemotherapy,
has significant unmet medical needs. Although no definitive treatment is currently available, various interventions are employed for HC. Effects of nonsurgical treatments for
HC are of modest success and studies aiming to control radiation-induced bladder symptoms are lacking. In this review, we present current and advanced therapeutic strategies
for HC to help cancer survivors deal with long-term urologic health issues.
[Rev Urol. 2016;18(2):57-65 doi: 10.3909/riu0700]
®
© 2016 MedReviews , LLC
KEY WORDS
Hemorrhagic cystitis • Radiation-induced cystitis • Hematuria • Cancer survivorship
A
s of January 2014, 14.5 million cancer survivors (excluding those with carcinoma-in-situ,
and basal and squamous cell skin cancers)
were living in the United States. This number is
expected to rise to 19 million by 2024.1 With this
increase in cancer survivors, cancer survivorship
medical and social issues are coming to the forefront. One rare but severely debilitating long-term
side effect of cancer therapy is hemorrhagic cystitis
(HC). Gorczynska and colleagues2 defined HC as the
presence of sustained hematuria and lower urinary
tract symptoms in the absence of active tumor and
other conditions, such as vaginal bleeding, general
bleeding diathesis, and bacterial or fungal urinary
tract infections. Urologic adverse events caused by
HC include frequency, dysuria, urgency, nocturia,
suprapubic pain, bladder infection, fatigue, and both
microscopic and gross hematuria. Bleeding from
HC ranges from nonvisible (or microscopic) hematuria to gross hematuria with clots.3 Moderately
severe cases of HC involve massive bleeding and
clot formation. Severe HC is a challenging condition to treat and may give rise to serious complications, leading to prolonged hospitalization and/or
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis continued
mortality.3 Even mild cases of HC
can cause disabling symptoms, such
as frequency, urgency and pelvic
pain, focused around the urethra.4
Other than surgery, chemotherapy and radiation therapy are
the most commonly used cancer
treatments, and both are risk factors for the development of HC.
Chemotherapy-induced HC can
be a side effect of treatment with
cyclophosphamide or ifosfamide.5
These cytotoxic agents are used
to treat a wide variety of cancers,
including lymphomas, leukemias,
sarcomas, germ cell tumors, blastomas, and carcinomas such as bladder, testicular, breast, endometrial,
ovarian, cervical, lung, and head
and neck cancer. Metabolism of
cyclophosphamide and ifosfamide
generates acrolein, a compound
that is secreted through the urine
and can cause urothelial damage
upon storage in the bladder.4 HC
can also result from pelvic radiation therapy. Radiation directly
delivers high-energy particles to the
tumor with limited systemic side
effects. However, some irradiationmediated damage to normal tissue
is inevitable. HC can be classified
as early or late onset,4 and develops
weeks to months after treatment in
20% to 25% of patients who receive
high-dose cyclophosphamide. The
effects of radiation-induced cystitis
(RC) can occur as early as 6 months
to as late as 20 years after radiation
treatment.6
represent subjective, objective,
management,
and
analytical
(SOMA) evaluation of late effects
to normal tissues (LENT). Each
individual organ or tissue known
to be within the target irradiation
zone, and thus at risk for radiation
damage, has its own LENT-SOMA
scale. This scale is based on the
original RTOG criteria for radiation morbidity.7 The LENT-SOMA
scale is a comprehensive system
Early symptoms of RC are thought to be due to damage to the
bladder urothelium, which has a low cell turnover and thus is
highly susceptible to irradiation-induced damage.
and provides much information,
but may be difficult to implement
in routine practice outside of clinical studies.8 Advances in radiation
therapy, such as high-energy linear
accelerators, conformal radiation
therapy, and intensity-modulated
radiation therapy, allow higher
doses of radiation to be delivered to
the tumor while sparing surrounding tissues. However, injury to nontarget organs is still prevalent.6
Radiation Cystitis
Pathophysiology
Although not well understood, the
inflammation seen in RC consists
of three distinct phases: (1) a short
acute phase that lasts up to several
weeks after radiation therapy; (2)
a symptom-free, dose-dependent
phase lasting months to years;
The effects of radiation-induced cystitis can occur as early as
6 months to as late as 20 years after radiation treatment.
Radiation Toxicity
Standardized
scoring
scales
were generated by the European
Organization for Research and
Treatment of Cancer and Radiation
Therapy Oncology Group (RTOG)
to calculate radiation toxicity in
different organs. These scales
therapy are expected to develop
RC.6
High-energy radiation can cause
cell death through direct absorption of radiation by DNA or indirectly through cell membrane
and DNA damage caused by free
oxygen radicals, formed through
radiolysis of water atoms.5,10 Early
symptoms of RC are thought to
be due to damage to the bladder
urothelium, which has a low cell
and (3) a chronic irreversible lateresponse phase.9 In 2014, approximately 60% of cancer survivors who
were men and 22% of cancer survivors who were women were previously treated for cancer located in
the pelvic region (eg, prostate, cervical, colon/rectal cancer). At least
5% of those treated with radiation
turnover and thus is highly susceptible to irradiation-induced damage.5,11 Exposure to urine can cause
additional irritability and inflammation of the bladder wall. Late
radiation injury can take several
months to many years to develop,
and is largely a function of the total
radiation dose and fraction size.
The pathologic hallmark of late
radiation tissue injury is obliterative endarteritis resulting in atrophy and fibrosis, and subsequently
necrosis of the bladder mucosa
and hematuria.12 Impaired healing under ischemic conditions can
lead to ulcer and fistula formation.
Telangiectasia (permanent dilation of blood vessels, usually in the
mucous membranes) develops, and
can also cause bleeding. Fibrosis
forms as part of the repair process
and, if severe, can lead to a reduction in bladder capacity (Figure 1).
Diagnosis
Clinical Presentation
Acute
RC-related
symptoms
include dysuria, increased urinary
frequency, and urgency. This condition may be self-limiting, and
persists up to 3 months after radiation therapy. Management is conservative, with symptomatic relief
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis
Radiation Therapy
Acute Phase
Latent Phase
Late Phase
Several weeks
Months to years
Chronic
UE
LP
D
ECM
Normal bladder
Endarteritis
Loss of GAG layer
Urothelial proliferation
ä Collagen deposition
Loss of urothelial cells
Leaky urothelium?
Fibroblast infiltration
Inflammation
å Smooth muscle cells
Edema
Endarteritis
Dilated blood vessels
Edema
Possible urine leakage
Hemorrhage
Stromal cell atypia
Inflammation
Pseudocarcinomatous
epithelial hyperplasia
Figure 1. Developmental stages of RC. RC progression consists of three phases: a reversible acute inflammatory phase, a latent symptom-free phase, and a late chronic
inflammatory phase. Each phase is characterized by specific pathologic changes that contribute to the symptoms associated with RC. D, detrusor; ECM, extracellular
matrix; GAG, glycosaminoglycan; LP, lamina propria; RC, radiation cystitis; UE, uroepithelium. Reprinted with permission from Zwaans BM et al.9
through anticholinergic drugs. Late
RC can develop from 6 months to
as late as 20 years after radiation
treatment has ended, with a mean
latent period of 35 months, according to one study.13
Pre-existing medical conditions,
including prior chemotherapy,
diabetes, hypertension, and previous unrelated abdominal surgery,
may put patients at increased risk
for RC. However, the most important risk factors are radiation treatment related, including volume of
main presenting symptom, and
can vary from mild to life-threatening. Hematuria with clot formation can lead to urinary retention.
The patient may also present with
other lower urinary tract symptoms such as pain, increased frequency, incontinence, and urgency.
Possible long-term consequences
of radiation on the urinary system
are listed in Table 1. Depending
on the etiology, patients may present with obstructive lower urinary
tract symptoms, including urinary
… the most important risk factors are radiation treatment
related, including volume of tissue treated, total bladder dose
and fractionation, mode of delivery (external beam and/or
brachytherapy), concurrent treatments, and radiosensitivity of the
affected bladder tissue.
tissue treated, total bladder dose
and fractionation, mode of delivery (external beam and/or brachytherapy), concurrent treatments,
and radiosensitivity of the affected
bladder tissue.10 Hematuria is the
retention secondary to detrusor
dysfunction and urethral stricture,
the latter being common in men
but rare in women. Urinary incontinence can be stress urinary incontinence due to intrinsic sphincter
TABLE 1
Radiation Damaging Effects
on the Urinary Tract
Ureter
Stricture
Vesicoureteral reflux
Fistulas
Ureteroenteric
Ureterovascular
Ureterovaginal
Bladder (Radiation Cystitis)
Lower urinary tract symptoms
Hematuria
Impaired bladder compliance
Bladder cancer
Fistulas
Urethra
Stricture disease
Stress urinary incontinence
Fibrosis
Fistula
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis continued
deficiency or urgency incontinence
as a result of small bladder capacity
and impaired detrusor compliance.
Patient Evaluation
Clinical features of late RC are nonspecific and overlap with symptoms
of bladder infection or malignancy.
Thus, diagnosis is focused on exclusion of other causes of hematuria.
Microscopic hematuria or urinary
tract infection can be detected
with urinalysis and urine culture.
Urine cytology may be considered
to detect high-grade malignancies.
Disease-focused history should
include details of radiation treatment the patient received, including total and daily dose, number
of sessions, and radiation delivery
technique. Physical examination
should focus on evaluating the
presence of possible vaginal fistulas. Postvoid residual volume can
diagnose underactive bladder and
a bladder diary provides an objective assessment of the patient’s
symptoms. Radiographic imaging of the kidneys with ultrasound
or computed tomography (CT)
is recommended and cystoscopy
can be performed to rule out urethral pathology, fistula, and cancer.
Bladder biopsy may be performed
if there is suspicion of tumor, but
should be done with great care to
avoid perforation of the irradiated
bladder wall or cause further bleeding. Urodynamic tests may help to
assess cystometric capacity, detrusor compliance, sphincter function,
and vesicoureteral reflux.4
Treatment
No standard of care therapy is
currently available for patients with
HC. There is also a lack of guidelines
available on optimal management.
Existing HC treatments are
regarded as ineffective, risky, or
both. Based on current knowledge,
Step 1
Grade 1
Minor
Grades 2 and 3
Moderate
Grade 4
Severe
Rest/Hydration
Clot evacuation/
Rest/Hydration
Hospitalization/
Hydration/Clot
evacuation
Continuous
irrigation
Cystoscopic
fulguration
HBOT
Blood
transfusion
BoNT
Lipo-tacro
Step 2
Step 3
Last Resort
Aminocaproic Acid
Alum
Prostaglandin
Formalin
Surgery
Figure 2. Treatment options for the management of HC. The preferred treatment option for HC is dependent
on the severity of hematuria. The first step in the treatment of HC is directed toward clot evacuation and
hydration to prevent further clot formation. If hematuria persists, continuous bladder irrigation, fulguration,
HBOT and, in case of excessive blood loss, blood transfusion should be considered. Novel therapies such as
BoNT injections and intravesical lipo-tacro could be implemented at this stage. If unresponsive to treatments,
patient should be subjected to intravesical instillations to arrest bleeding. As an absolute last resort, surgery
should be considered. BoNT, botulinum toxin; HBOT, hyperbaric oxygen therapy; HC, hemorrhagic cystitis;
lipo-tacro, liposome tacrolimus.
the suggested treatment options for
HC are reviewed here (Figure 2).
Clot Evacuation and
Fulguration
After diagnosis, the choice of therapy depends on the degree of hematuria, and a stepwise approach to
treatment should be taken.4 The
first step in the treatment of HC is
directed toward clot evacuation.14
Bladder outlet obstruction from
clots can lead to sepsis and bladder rupture. Clot evacuation is performed by placing a wide-lumen
bladder catheter followed by bladder irrigation with water or sodium
chloride solution.4
After clot evacuation, patients
should be hydrated using intravenous fluids to prevent clot
reformation. If hematuria persists,
continuous bladder irrigation
can be started through a threeway catheter.14 All clots must be
removed before starting continuous
irrigation to avoid overdistention
and potential bladder ruptures.5 If
clot evacuation remains unsuccessful, the patient should undergo cystoscopy with clot evacuation and
fulguration of bleeding sites.
Cystoscopic Fulguration. Cystoscopy with fulguration of bleeding points is an effective method
of treating HC that is unresponsive to conservative measures.15
This procedure can be performed
under local anesthesia, especially
in women. Methods of fulguration
include the use of electrocoagulation, diathermy, and several types of
lasers.16,17 Potential morbidity following cystoscopy and cystoscopy
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis
with fulguration includes bladder
perforation with subsequent fistula formation.18 More severe cases
of HC often do not respond to this
treatment modality.
Hyperbaric Oxygen Therapy
Hyperbaric
oxygen
therapy
(HBOT) has been used in case studies for the management of HC. The
hyperbaric oxygen chamber provides conditions at which hemoglobin is fully saturated and oxygen
is dissolved at very high levels in
the blood plasma, providing therapeutic benefits such as increased
angiogenesis and fibroblast activity in damaged tissues.19 Therefore,
HBOT can be considered as an
alternative treatment for patients
with underlying ischemia that is
Patients with epilepsy must be
sedated because oxygen stimulates
the central nervous system. When
a patient presents with a fever of
unknown origin, the etiology must
be found before start of therapy.22,23
Intravesical Instillation
If hematuria persists after the
treatments described above, bladder instillation can be performed
with astringent intravesical agents,
including 1% silver nitrate or aluminum sulfate (alum).4 Although
the mechanisms of action of these
agents vary, the general principles
are sterilization, lavage, and arrest
of focal bleeding points. The most
commonly used agents are alum
and formalin.
… HBOT can be considered as an alternative treatment for patients
with underlying ischemia that is unresponsive to conventional
therapy.
unresponsive to conventional therapy. Various HBOT regimens have
been used: in general, 100% oxygen
is administered at 1.5 to 2.5 atm for
45 to 120 minutes, allowing extra
time for compression and decompression. Sessions are once daily
for a predetermined length of time
(usually 20-40 sessions).9
An advantage of HBOT in HC
patients is the absence of adverse
effects on bladder structure or
function that may occur with other
therapies (eg, formalin or silver
nitrate instillation), while avoiding
surgery. However, HBOT is a timeconsuming treatment with variable
reported response rates (27%-92%)
and relatively high recurrence rates
(8%-63%).20-23 Side effects of HBOT
include oxygen toxicity, which
is rare (eg, seizures and alveolar
membrane damage), confinement
anxiety, ear pain, and digitalis toxicity (if taking drugs). HBOT is not
advised in pregnant women as it
may increase erythrocyte fragility.
Aminocaproic Acid. Treatment
with epsilon aminocaproic acid,
a drug used to treat excessive
renal insufficiency as increased
levels can cause encephalopathy and acidosis.26 Local adverse
effects include suprapubic pain
and vesical tenesmus. These can
be controlled with antispasmodic
and/or analgesic drugs.27
Prostaglandins. Intravesical prostaglandins are also used to treat
HC. Prostaglandins are cytoprotective and have anti-inflammatory
and vasoconstriction properties,
but may cause flushing or severe
bladder spasms.28
Formaldehyde (Formalin). Res-
erved for severe and intractable
HC, formaldehyde instillation
hydrolyzes protein and coagulates
superficial bladder mucosa tissue.
When considering formalin instillation, it is important to first rule
out vesicoureteral reflux. If present,
one may proceed only after placing
occlusive balloon catheters in each
ureter as reflux can lead to bilateral
pyelonephrosis with fatal sepsis.29
Formalin has been used in patients
with severe refractory RC.29-31
Reserved for severe and intractable HC, formaldehyde instillation
hydrolyzes protein and coagulates superficial bladder mucosa
tissue.
postoperative bleeding, has been
reported in HC.24 However, it can
result in the formation of large, hard
clots that are difficult to remove.
These clots can cause upper tract
bleeding and loss of the respective
renal unit.24
Alum. Aluminum salts, such as
alum, are astringent agents that
act by precipitating proteins on
the cell surface and in interstitial spaces. Capillary bleeding
is arrested in mild cases, but in
severe cases the precipitant tends
to clot, resulting in clot retention,
distension and more hemorrhaging.25 Aluminum levels must be
closely monitored in patients with
Intravesical formalin instillation is
performed under general or local
anesthesia. It causes precipitation
of cellular proteins in the mucosa,
thereby occluding and fixing telangiectasia tissue and small capillaries. However, fixation of the bladder
musculature may result in a small,
contracted bladder, and fixation of
the intramural ureter can also lead to
obstruction with subsequent hydronephrosis and renal failure. The
most critical factor is administering
the proper formalin dilution (1%-4%
for 10-30 min is traditionally used).5
Formalin is toxic even in very dilute
(1%) concentration.29 In a retrospective study, 1% formalin solution was
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis continued
equally effective in arresting bleeding as 2% or 4% solution, but caused
fewer complications. Treatment
of hematuria with 10% formalinsoaked pledgets has been reported
to be equally effective in arresting
bleeding as 4% formalin instillation,
with minimal side effects.32 On the
contrary, instillation of 5% and 10%
formalin solutions have been associated with increased morbidity and
mortality.29
Surgical Interventions
In patients with refractory HC,
surgical intervention is warranted.
More aggressive treatment options
patients with comorbidities, surgery should be considered as a last
resort for refractory HC.36
Developing Treatment
Modalities for
Hemorrhagic Cystitis
Botulinum Toxin
Botulinum toxin (BoNT) blocks
acetylcholine release at neuromuscular junctions, and bladder injection of BoNT is now an approved
therapy for neurogenic and idiopathic detrusor overactivity.37
Recent research has shown that
More aggressive treatment options to arrest bleeding include
selective embolization or ligation of the iliac or bladder arteries.
to arrest bleeding include selective
embolization or ligation of the iliac
or bladder arteries.33 Several urinary diversion methods have been
used, including temporary bladder
exteriorization with packing of the
bladder and ileal conduit diversion. Reports suggest that a transverse colon conduit is the preferred
method of urinary diversion, which,
in RC patients, has the advantage of
using the nonirradiated bowel and
ureters for creating the diversion.
Alternative options for urinary
diversion include percutaneous
nephrostomy and cutaneous ureterostomy.34 Complications related
to the defunctionalized bladder,
including pyocystitis, hemorrhage,
pain, and neoplastic transformation, occur in over 50% of patients
who have undergone urinary diversion35; therefore, cystectomy is recommended at the time of urinary
diversion. Preoperative high-dose
radiation therapy is a risk factor for
postoperative morbidity, particularly enteroenteric fistulas, urointestinal fistulas, and stenosis of the
ureterointestinal
anastomosis.35
Because of the high morbidity and
mortality risk, especially in elderly
it also limits muscle contraction
by inhibiting the release of neurotransmitters and the expression
of the TRPV1 receptor, and that it
suppresses bladder inflammation
by preventing the expression of EP4
receptors and cyclooxygenase-2.38,39
Chuang and colleagues40 used
BoNT type-A injections as a treatment for RC in six patients refractory
to other treatments. Under sedation
or local anesthesia, 200 U BoNT
type-A was submucosally injected
through a cystoscope into 20 sites in
the trigone and floor of the bladder.
No side effects were noted from the
injections. A moderate to significant improvement was achieved in
five of the six patients, with mean
bladder capacity increasing from
105 mL to 250 mL and mean urinary frequency decreasing from
14 to 11 episodes per day. Although
further studies are needed, BoNT
injection is a promising therapy to
treat patients with RC.40
Intravesical Instillation of
Liposome-Tacrolimus
Tacrolimus has been approved
by the US Food and Drug
Administration as a systemic
therapy for inhibiting transplant
rejection and as topical ointment
for moderate to severe atopic dermatitis. Tacrolimus acts by inhibiting interleukin (IL)-2-dependent
T-cell activation and has a direct
inhibitory effect on cell-mediated
immunity. Tacrolimus is not water
soluble, but can be dissolved in
hydrophobic solvents.41 The application of liposomal tacrolimus in
HC has two targets: (1) tacrolimus
inhibits T-cell activation, and (2)
tacrolimus causes acute arteriole
vasoconstriction.
Mode of Action. Tacrolimus
prolongs the survival of the host
and transplanted graft in animal
transplant models of liver, kidney, heart, bone marrow, small
bowel and pancreas, lung and
trachea, skin, cornea, and limb.
Furthermore, it is occasionally
used in the treatment of various
immune-mediated diseases. In animals, tacrolimus has been demonstrated to suppress some humoral
immunity and, to a greater extent,
cell-mediated reactions such as
allograft rejection, delayed type
hypersensitivity, collagen-induced
arthritis, experimental allergic
encephalomyelitis, and graftversus-host disease.42
Tacrolimus is a macrolide antibiotic and acts primarily on T-helper
cells, although some inhibition of
suppressor and cytotoxic T-cells
also seems to occur. Through
binding with the FK506-binding
protein (FKBP-12), tacrolimus is
a competitive inhibitor of calcineurin, a calcium- and calmodulin-dependent phosphatase. This
process inhibits the translocation of the NF-AT (nuclear factor of activated T-cells) family of
transcription factors, leading to
reduced transcriptional activation of early cytokine genes for
IL-2, interferon-ɣ, tumor necrosis
factor-α, IL-3, IL-4, CD40L, and
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis
Tacro
Tacro
Lipo
CYP
Tacro
FKBP-12
Acrolein
FKBP-12
P
–
CMD
+
Ion
Channel
Ca2+
NF-AT
Calcineurin
Ca2+
P
P
+
+
NF-AT
Acrolein
Nucleus
+
LP
NF-AT
Co
IL-2, TNFα,
IL-3, IL-4
CD40L, ...
Co
Cytoplasm
Figure 3. Schematic illustration of the anti-inflammatory function of tacrolimus in HC. Irradiation-induced lipid peroxidation and CYP metabolism are sources of acrolein. Acrolein enhances Ca2+ absorption, which in turn stimulates calcineurin to dephosphorylate and activate NF-AT. Once activated, NF-AT moves to the nucleus
where it induces transcription of pro-inflammatory cytokines. Tacrolimus inhibits NF-AT activity by binding to calcineurin and preventing the dephosphorylation of
NF-AT. CMD, calmodulin; Co, transcriptional co-factor; CYP, cyclophosphamide; FKBP-12, FK506-binding protein; Lipo, liposome; NF-AT, nuclear factor of activated
T-cell; Tacro, tacrolimus; TNF, tumor necrosis factor.
granulocyte-macrophage colonystimulating factor (Figure 3).43
Ultimately, proliferation of lymphocytes is reduced. Cyclosporine
is an immunosuppressant that also
prevents calcineurin from dephosphorylating and activating NF-AT.
Although the mode of action of
tacrolimus is similar to that of
cyclosporine, tacrolimus has been
shown to be less nephrotoxic than
cyclosporine.44
Effect of Liposome-tacrolimus
on
Hemorrhagic
Cystitis
Animal Models. The urothe-
lium is the primary site of tissue
damage in the pathophysiology
of cystitis.45,46 Recent studies have
highlighted overexpression of
genes related to immunity and
inflammation, including activation of CD4+ T-helper type-1related chemokines in cystitis.47
Nirmal and associates43 examined levels of tacrolimus in blood,
urine, and bladder tissue of rats
following exposure to combination
liposome-tacrolimus (lipo-tacro) or
The efficacy of lipo-tacro was
examined in a model of RC in
which rats received a single dose of
40 Gy delivered directly to the bladder using a three-beam CT-targeted
irradiator. Radiation treatment
significantly reduced intermicturition intervals, which was successfully reversed with a single dose of
Bladder instillation of lipo-tacro significantly decreased systemic
exposure in comparison with intraperitoneal delivery of
tacrolimus.
tacrolimus. Bladder instillation of
lipo-tacro significantly decreased
systemic exposure in comparison
with intraperitoneal delivery of
tacrolimus.
intravesical lipo-tacro. Six weeks
after irradiation, saline-treated
rats showed edematous changes
with inflammatory cell infiltration and hyperplastic urothelium.
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis continued
In contrast, lipo-tacro treatment
showed
minimal
edematous
changes.48 Lipo-tacro also reduced
urinary frequency and suppressed
inflammation and edema in the
bladder mucosa and submucosal
layers of a rat model of chemotherapy-induced HC.49 These studies
indicate that lipo-tacro is a promising novel treatment for radiationand chemotherapy-induced HC.
Clinical Experience. Lipo-tacro
has not been tested in clinical
subjects; however, we recently
reported a compassionate use
case of intravesical tacrolimus
alone in an 81-year-old man
with a history of external beam
radiation therapy for the treatment
of localized prostate cancer.50
The patient has a medical history
of atrial fibrillation, coronary
artery disease, congestive heart
failure, apnea, hypothyroidism,
and gastrointestinal bleeding. No
prostate cancer recurrence was
noted, but the patient developed
progressive HC. Past treatments
included HBOT, though without
adequate or sustained symptom
relief.
During the months prior to
treatment, the patient required
outpatient visits due to gross
hematuria. He was admitted
to the hospital twice for nearly
30 days requiring catheterization,
bladder irrigation, 8 units of blood
transfusion for anemia, antibiotics
for urinary tract infection, and
two surgeries for fulguration of
bleeding. Gross hematuria did not
resolve, and bladder instillation of
formalin was being considered as
a last resort. The patient, family,
and medical team had concerns
of adverse events associated with
formalin and elected intravesical
tacrolimus instillation.
The patient received two
instillations on consecutive days
that were well tolerated. Blood
tacrolimus levels were 0.8 ng/mL
and 2.3 ng/mL 24 hours after
instillation respectively (reference
range 5.0-15.0 ng/mL). The patient’s
gross hematuria diminished and
the patient was discharged without
gross hematuria after an additional
48 hours of observation. During
the next 6 months the patient was
able to stay at home without further
hematuria.
Stakeholders in Cancer
Survivorship and
Radiation Cystitis
Despite a growing interest in RC
by both the public and medical
community, RC is not globally recognized and remains underinvestigated. Patients and their families
with this terrible condition are
in desperate need of novel therapies and support. The Radiation
Cystitis Foundation (http://www
.radiationcystitis.org/) is a nonprofit patient advocacy group
working to help improve the lives
of all those affected by radiation
and to advance treatment of RC.
The Radiation Cystitis Foundation
is the first organization dedicated
entirely to RC and consists of a
group of dedicated volunteers.
MAIN POINTS
• Hemorrhagic cystitis (HC) is a rare but serious disease that may affect patients after pelvic radiation or systemic
chemotherapy. No standard of care therapy is currently available for patients with HC.
• Although not well understood, the inflammation seen in radiation cystitis (RC) consists of three distinct phases:
(1) a short acute phase that lasts up to several weeks after radiation therapy; (2) a symptom-free, dosedependent phase lasting months to years; and (3) a chronic irreversible late-response phase.
• The first step in the treatment of HC is directed toward clot evacuation and hydration, followed by bladder
irrigation and/or cystoscopic fulguration of bleeding points if hemorrhaging persists.
• Hyperbaric oxygen therapy (HBOT) has been used in case studies for the management of HC. HBOT can
be considered as an alternative treatment for patients with underlying ischemia that is unresponsive to
conventional therapy.
• Reserved for severe and intractable HC, formaldehyde instillation hydrolyzes protein and coagulates superficial
bladder mucosa tissue. When considering formalin instillation, it is important to first rule out vesicoureteral
reflux.
• Promising novel therapies, such as intravesical instillation of liposomal formulation of tacrolimus, improves
local drug delivery and may treat the underlying condition of HC.
64 • Vol. 18 No. 2 • 2016 • Reviews in Urology
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Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis
Conclusions
Time is of the essence for patients
with HC as no adequate treatment
options are available. New therapies, such as intravesical lipo-tacro
formulation, are being investigated
for the treatment of this rare but
serious disease with unmet medical
needs.
Bernadette M.M. Zwaans is a Urology Care
Foundation Scholar. Michael B. Chancellor is
the founder and Chief Scientific Officer of Lipella
Pharmaceuticals, Inc. (Pittsburgh, PA). The
remaining authors declare no relevant conflicts
of interest.
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